Blended Inheritance As a Genetic Consequence of Unlimited Regeneration

混合遗传是无限再生的遗传结果

• 批准号: 8322615
• 负责人: Sergey V Nuzhdin
• 金额: $ 32.8万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8322615
• 关键词: Adult; Affect; Animals; Back; Biological Models; Biomedical Engineering; Cell Communication; Cell Differentiation process; Cells; Communication; Communities; Conflict (Psychology); DNA Resequencing; Data; Development; Dugesia (turbellarian); Employee; Employee Strikes; Equilibrium; Escherichia coli; Evolution; Fresh Water; Future; Gene Expression Profile; Generations; Genetic; Genetic Identity; Genetic Models; Genetic Variation; Genome; Genomics; Germ Cells; HIV; Health; Heterogeneity; Human; Individual; Karyotype; Knowledge; Laws; Learning; Longevity; Malignant Neoplasms; Measurement; Mediating; Meiosis; Meristem; Messenger RNA; Modeling; Molecular Genetics; Mutation; Natural regeneration; Nature; Organ; Organism; Pathway interactions; Patients; Planarians; Plants; Pluripotent Stem Cells; Population; Population Genetics; Population Sizes; Process; Proliferating; RNA Sequences; Regulation; Reproduction; Research; Research Personnel; Route; Sampling; Secure; Staging; Stem cells; Subgroup; Technology; Testing; Time; Tissue Donors; To specify; Totipotent Stem Cells; Variant; Wages; Work; asexual; cancer cell; cell motility; cell type; experience; fly; genetic analysis; human tissue; insight; interest; models and simulation; next generation; prevent; regenerative; reproductive; research study; stem cell differentiation; systems research; theories; tissue regeneration; transplantation medicine

DESCRIPTION (provided by applicant): The Century of untangling the laws of Genetics, and molecular nature of developmental regulation was enabled by inspired choice of workhorse models: from E. coli to M. domesticus. All of them abide to the rules of Mendelian inheritance, making the genetic analyses in them logical and straightforward. The reproductive interests of cells constituting these organisms are aligned due to a single cell bottleneck during reproduction. These principles do not work for cancer cells, which have accumulated mutations promoting reproduction. These cells are 'interested' in reproducing at the expense of other non-cancer cells, thereby harming the 'host organism'. This scenario illustrates a typical 'conflict' between multi-player communities - be it heterogeneous HIV viruses multiplying within a patient, shortening their lifespan, or employees hurting the competitive ability of a company by striking for a greater salary. Planarians are a popular model for the analyses of regeneration. Regeneration will, in the future, enable dramatic advances in human health. By necessity, regeneration will result in an organism consisting of heterogeneous genomes of cells. Just as donor-tissue rejection has been a problem in transplant medicine, when regeneration technologies become advanced, a problem will be in the lack of communication and cooperation between cells. Traditional genetic models are inadequate for deciphering the rules of intraorganismal conflicts and cell mis-communication, but planarians are. They are typically either sexual or parthenogenetic - both processes involving meiosis and a genome bottleneck. However, when a planarian lineage encounters a mutation abolishing meiosis, it can still happily survive. This is due to the planarian unrestricted regenerative ability. Planarians can be cut in any axial orientation and complete regeneration of all absent adult anatomical features occurs. In the 1970s, Dugesia gonocephala planarian populations that are fixed for meiosis-compromising mutations were discovered. These populations reproduce exclusively by fission. Additional samples of planarians from these Italian populations were secured and brought to the PI's lab in 2010. They still reproduce explicitly by transverse fission with subsequent regeneration. They must represent 'genomic quilts', where individuals are made of multiple genetically heterogeneous cell population types. How much intraindividual genetic variation do they possess? How do planarians resolve reproductive conflicts among cells in the process of pluripotent cell migration and differentiation? How do planarians mediate communication and coordination problems between genetically heterogeneous cells? Deep sequencing of individuals genomes, mRNA sequencing of individual pluripotent cells in the process of differentiation, and approximate Bayesian computations will be used to answer these and other questions. Morgan's first experiments in Genetics were with planarians, but he switched to a simpler fly model to describe the laws of Mendelian inheritance. It is time now to come back to the model of blended inheritance, in which hundreds of thousands of genomes are transmitted from generation to generation.

描述（由申请人提供）：通过启发的士兵选择模型的选择来实现遗传学定律的世纪和发育调节的分子性质：从大肠杆菌到毒品。他们所有人都遵守孟德尔继承的规则，使它们的遗传分析逻辑且直接。构成这些生物的细胞的生殖兴趣是由于繁殖过程中单个细胞瓶颈而对齐的。这些原理不适用于促进繁殖突变的癌细胞。这些细胞“感兴趣”以牺牲其他非癌细胞为代价，从而损害“宿主有机体”。这种情况说明了多人社区之间的典型“冲突” - 无论是在患者中繁殖的异质HIV病毒，缩短其寿命，还是员工通过攻击更高的工资来伤害公司的竞争能力。平面主义者是复兴分析的流行模型。将来，再生将在人类健康方面取得巨大进步。必要时，再生将导致由细胞的异质基因组组成的生物。正如捐助者组织的拒绝是移植医学的一个问题一样，当再生技术提高时，问题也将是细胞之间缺乏沟通和合作的问题。传统的遗传模型不足以破解生物内冲突和细胞错误交流的规则，但平坦的人是。它们通常是性的或孤生的 - 两种涉及减数分裂和基因组瓶颈的过程。但是，当一个平谱系遇到消除减数分裂的突变时，它仍然可以幸福地生存。这是由于普拉纳尔无限制的再生能力所致。可以在任何缺乏成人解剖特征的所有轴向取向中切割平面的人。在1970年代，发现了针对减数分裂 - 强化突变的dugesia gonocephala planary种群。这些人群仅通过裂变繁殖。从这些意大利人群中获得的其他平面人的样本得到了保护，并于2010年将其带到PI的实验室。他们仍然通过横向裂变明确繁殖，随后再生。它们必须代表“基因组被子”，其中个体由多种遗传异质细胞群体组成。他们拥有多少个内部遗传变异？在多能细胞迁移和分化的过程中，平面主义者如何解决细胞之间的生殖冲突？平面主义者如何介导遗传异质细胞之间的沟通和协调问题？对个体基因组的深度测序，在分化过程中单个多能细胞的mRNA测序以及近似贝叶斯计算将用于回答这些问题和其他问题。摩根在遗传学方面的第一个实验是在平面主义者中，但他改用了更简单的苍蝇模型来描述孟德尔遗传的定律。现在是时候回到混合遗传的模型，其中成千上万的基因组一代传播。